Medical treatment of resistant or recurrent epithelial ovarian cancer.

Epidemiologic analysis reveals that mortality rates from ovarian cancer are continuously decreasing due to the improvement of surgery and chemotherapy. However, overall, the prognosis of ovarian cancer patients is still unsatisfactory considering that only 30% of the patients are alive after 5 years. In fact, although surgery and first-line systemic chemotherapy induce complete and partial response in up to 80% of patients, with about a 25% pathological complete remission rate, recurrences occur in the majority of patients. Most of these patients are subject to repetitive treatment cycles that, although palliative in nature, are also able to prolong survival. Important results have been obtained, in particular in platinum sensitive recurrent disease where a platinum base chemotherapy is able to prolong progression-free survival and overall survival. Overall, our armamentarium for the treatment of progressive or recurrent ovarian cancer is significantly richer than in the past, and in many patients it is possible to achieve the objective to reach a chronic history of the disease.

An escalating dose finding study of liposomal doxorubicin and vinorelbine for the treatment of refractory or resistant epithelial ovarian cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD) of liposomal doxorubicin (LD)-vinorelbine (V) in patients with refractory or resistant ovarian cancer. PATIENTS AND METHODS: Thirty patients were eligible. Seven levels were studied [LD 25-V20 (three patients enrolled); LD 30-V20 (three); LD 35-V20 (three); LD 20-V25 (three); LD 25-V25 (three); LD 30-V25 (10); LD 35-V25 (five)]. LD was given on day 1, while V was given on days 1 and 8 every 21 days. Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. RESULTS: DLT was observed in four patients: two febrile neutropenia, one grade 4 thrombocytopenia and one grade 3 palmar-plantar erythrodysesthesia (PPE) at level 7 (LD 35-V25). Thus, liposomal doxorubicin 30 mg/m(2) plus vinorelbine 25 mg/m(2) was the MTD. The most frequent toxicity was neutropenia. Fifteen patients (50%) experienced grade 3 neutropenia and 10 (33.3%) grade 4 neutropenia. Non-hematological toxicity was mild. Mucositis and PPE were the most frequent toxicities, but in most cases were grade 1. Out of 29 assessable patients, six (20.7%; 95% confidence interval 10%-39%) experienced an objective response, with one complete response. CONCLUSIONS: In patients with refractory or resistant ovarian cancer, the recommended doses for the combination studied are liposomal doxorubicin 30 mg/m(2) (day 1) plus vinorelbine 25 mg/m(2) (day 1 and 8). Neutropenia is the most frequent toxicity, while non-hematological toxicity is mild. Substantial activity was recorded and a phase II study is justified.

Very high-dose chemotherapy with autologous peripheral stem cell support in advanced ovarian cancer.

20 patients with stage III-IV ovarian cancer were submitted to induction chemotherapy (ICT) (40 mg/m2 cisplatin, days 1-4; 1.5 g/m2 cyclophosphamide, day 4; every 4 weeks for 2 cycles) followed by intensified CT (100 mg/m2 cisplatin, day 1; 650 mg/m2 etoposide, day 2; 1.8 g/m2 carboplatin by 24 h infusion, day 3). Haematological support consisted of autologous peripheral stem cells (APSC) and bone marrow (ABM) transplant (T) in 16 and 4 patients, respectively. All patients were evaluable for toxicity and 19 for pathological response (PR), one patient dying of systemic mycosis after ABMT. Severe (grade 3-4) non-haematological toxic effects were gastrointestinal (100%), neurological (10%) and hepatic (10%). PR was observed in 84% of patients (complete response 37%, partial response with microscopic residual disease 26%, partial response with macroscopic residual disease 21%). Five year overall survival was 60% and progression-free survival was 51% with 9 patients still disease-free (DFS). APSCT significantly reduced the duration of aplasia compared with ABMT, and toxicity was acceptable in those patients undergoing APSCT. The prolonged DFS in patients showing PCR suggests that this new approach may have a therapeutic impact.

Recombinant alpha-2b-interferon dynamic test as a potential tool in predicting disease status during second look in ovarian cancer. A preliminary report.

The circulating levels of a 90-kilodalton (KD) tumor-associated antigen were measured in the blood of 26 patients with ovarian cancer in clinical remission who received a short course of recombinant alpha-2b-interferon (rIFN-alpha-2b, 3 million U/m2/d intramuscularly for 3 days) before second-look procedures. The administration of rIFN-alpha-2b to 90-KD antigen-positive patients produced a slight increase of the marker. However, in patients without the marker but with evidence of disease, a remarkable increase above the cutoff level was observed. Less pronounced modifications of 90-KD antigen serum levels were found in patients with no disease at second look. Moreover, considering the 90-KD antigen mean percentage increase, the dynamic test with rIFN-alpha-2b was able to eliminate five of six false-negative results obtained with the 90-KD antigen basal assay alone. The sensitivity of the assay increased to 92% after IFN compared with 54% for the 90-KD antigen assay alone. An increase (greater than 100% above pretreatment titer) of 90-KD antigen levels during the test also was observed in four patients with no evidence of disease at second look. In two of these false-positive cases, recurrence of disease was observed 13 and 24 months later. At the time of this analysis, none of the patients with a negative second look and negative dynamic test had relapsed. These results suggest that the dynamic test with rIFN-alpha-2b might be a new tool to assess disease status in patients with ovarian cancer before second-look procedures.

Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer. Prognostic factors for response and survival.

Between January 1986 and September 1988, 75 patients with locally advanced cervical carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stages IB-III) received three courses of neoadjuvant chemotherapy (NAC), including cisplatin, bleomycin, and methotrexate (PBM). Fifteen percent of patients achieved a complete response (CR) and 68% a partial response (PR). Pretreatment characteristics were analyzed for response to NAC. Significantly lower response rates were found in patients with tumor size more than 5 cm in diameter and bilateral parametrial involvement to the pelvic side wall. None of the biological parameters studied was related to chemoresponsiveness. Patients achieving CR or PR had a significantly improved 3-year survival rate compared with those who did not respond. After NAC, radical surgery was possible in all responding patients. The median number of lymph nodes removed was 60. A lower than expected incidence of lymph node metastases was detected. None of the clinical and pathologic features considered was significantly correlated with the lymph node status. Twelve of the 62 operated patients had disease recurrence. Pathologic parametrial involvement and cervical infiltration equal to or deeper than 5 mm were found to be significant prognostic factors for recurrence. A 3-year, disease-free survival of 89%, 73%, and 43% for Stage IB-IIA, IIB, and III, respectively, was found. Among the operated patients these rates increased to 100%, 81%, and 66% for Stage IB-IIA, IIB, and III, respectively. A prospective randomized trial comparing NAC and surgery with radiotherapy alone is in progress.

Ovarian carcinoma: an ultrasound study.

Between March 1986 and March 1989, 65 epithelial ovarian carcinomas were studied by means of real time high resolution ultrasound. The sonographic findings were correlated with FIGO stage, histotype and histological grade. The echostructure was compared with that of a group of 141 benign controls. Moreover, some sonographic patterns, significantly more frequent in the malignant tumors (ascites, irregular borders, peritoneal growths), were identified. The diagnosis of malignancy was as accurate as 90.0%, sensitivity and specificity were 84.7% and 92.3% respectively. Our results, coupled with the low costs involved and the non-invasiveness of the method, thus confirm that ultrasound can still be considered a primary technique in the preoperative assessment of ovarian masses.

Rationale for very high-dose chemotherapy with peripheral blood stem cell support in advanced ovarian cancer.

Although significant progress has been made in the management of advanced ovarian cancer, the majority of patients continue to die of this disease. Most advanced ovarian cancer patients present sub-optimal residual tumour after primary surgery and their prognosis is very poor since residual disease has been confirmed as the major factor predicting response to chemotherapy and survival. Therefore, it seems worth developing treatment modalities that can produce a longer remission period. In this short review, the authors summarize the clinical and experimental evidence supporting the usefulness of high-dose chemotherapy with autologous peripheral blood stem cell transplantation in advanced ovarian cancer.